Endomyocardial biopsy in right ventricular cardiomyopathy

International Journal of Cardiology, 40 (1993) 213-282

@ 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. 0167-5273/93/$06.00 213

CARD10 01733

Endomyocardial biopsy in right ventricular cardiomyopathy

Annalisa Angelini”, Gaetano Thiene”, Giovanni M. Boffab, Irene Calliaris”, Luciano Dalientob, Marialuisa Valentea, Raffaello Chioinb, Andrea Navab,

Sergio Dalla Voltab

“Department of Pathology and bDepartment of Cardiology, University of Padua Medical School and ‘C. U.G. A.S., Padua, Ital)

(Received 16 November 1992; revision accepted 22 February 1993)

Right ventricular cardiomyopathy is characterized by a progressive myocyte loss and fibro-fatty substitution of the right ventricle. The aim of our study was to assess the diagnostic accuracy of right ventricular endomyocardial biopsy. Using an imaging analyser system, histomorphometric parameters of myocytes, interstitium, fibrous tissue and fatty tissue were evaluated on endomyocardial biopsy from 30 patients with arrhythmogenic right ventricular cardiomyopathy, 29 patients with dilated cardiomyopathy and 30 control patients. The percent area of myocytes decreased from 78.10 + 7.34 in control to 63.39 f 9.22 in dilated cardiomyopathy (P < 0.05) and to 47.28 f 15.01 in arrhythmogenic right ventricular cardiomyopathy (P < 0.01). Fibrous tissue increased from 8.10 f 3.89 in control to 21.80 f 9.29 in dilated cardiomyopathy (P < 0.05) and to 24.60 f 11.37 in arrhythmogenic right ventricular cardiomyopathy (P < 0.05). Fatty tissue varied from 0.33 A 1.44 in control and 0.07 f 0.31 in dilated cardiomyopathy to 13.30 f 17.30 in arrhythmogenic right ventricular cardiomyopathy (P c 0.05). Fatty tissue was a feature of arrhythmogenic right ventricular cardiomyopathy (67% of patients vs. 6% of control and dilated cardiomyopathy patients). Diagnostic values typifying arrhythmogenic right ventricular cardiomyopathy, obtained by excluding any overlapping between confidence intervals in the three groups, were: myocytes ~44.95%; fibrous tissue >40.38%, and fatty tissue > 3.21%, ‘with 67% sensitivity and 91.53% specificity for at least one parameter. In conclusion, a significant difference between arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy and control exists in terms of amount of myocytes, fibrous tissue and fatty tissue. Presence of fatty tissue and fibrous tissue exceeding 3.21% and 40.38%, respectively should be considered highly suspect for arrhythmogenic right ventricular cardiomyopathy in right ventricular endomyocardial biopsy.

Key words: Cardiomyopathy; Endomyocardial biopsy; Right ventricular cardiomyopathy; Histo- morphometry

Introduction

Right ventricular cardiomyopathy is a myocardial disease characterized by a progressive

Correspondence 10: Gaetano Thiene, M.D. Istituto di Anatomia Patologica, Via A. Gabelli, 61 35121 Padova, Italy.

myocyte loss and libro-fatty atrophy of the right ventricle, which clinically accounts for electrical instability, ominous ventricular arrhythmias and even sudden death [l-9].

Morphological diagnosis is potentially achiev- able in vivo by right endomyocardial biopsy because: (1) the right ventricle is electively affected

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and is easily reached by the transvenous bioptome; (2) the ~brous-fatty transfo~ation of the right ventricle is almost completely transmural, and thus may be detected in biopsy samples from the endomyocardial side; (3) the histopa~oIogic pat- terns of fibrous or fatty tissue replacement of the myocardium are readily recognized at light microscopy. Nonetheless, the presence of fatty or fibrous tissue in endomyocardial biopsy is not a patho~omonic feature [IO-121, nor have quantitative techniques been used to date to define precise diagnostic histologic criteria.

The aim of this study was to establish the sensitivity and specificity of histomorphometric parameters using a new morphometric method, in order to assess the diagnostic accuracy of right ventricular endomyocardial biopsy in right ventricular cardiomyopathy.

Material and Methods

Eighty-nine patients subdi~ded into three different groups, according to the clinical diagnosis of right ventricular cardiomyopathy (30 patients), dilated cardiomyopathy (29 patients), and normal control (30 patients) were studied. The clinical diagnosis was achieved by means of electrocar- diographic, echocardiographic and angiographic investigations.

Controls consisted of 30 consecutively trans- planted patients, at the time of their first endomyocardial biopsy (7 days after operation). We assumed that the heart graft from a young donor would be normal in terms of its fibro-fatty com- ponents.

Dilated cardiomyopathy was diagnosed by cardiac catheterization in the presence of increased left ventricular volumes and reduced ejection fraction. Coronary artery, valvular and specific myocardial diseases were excluded in all cases. Left ventricular end-diastolic volume ranged from 122 to 392 ml/m’ (mean 190.91 f 64.1 ml/m2), and ejection fraction from 47 to 10% (mean 27.3 f 10.2%). The left ventricular end-diastolic pressure ranged from 6 to 35 mmHg (mean 20.85 f 7.55). The cardiac index ranged from 1.2 to 4.1 Ymin per m2 (mean, 2.57 f 83).

The diagnosis of right ventricular cardiomyopathy was formulated in patients with ventricular arrhythmias, a left bundle branch block pattern and T-wave abno~alities in precordiai leads. The morphological diagnosis was based on echocardiographic [4] and angiographic [7] documenta- tion of localized or widespread structural and dynamic abnormalities involving exclusively or mainly the right ventricle, and unrelated to valve disease, shunts, active myocarditis, coronary artery disease or pulmonary hypertension. In par- ticular, these cases were distinguished from dilated cardiomyopathy because the left ventricle never exhibited diffuse dynamic impairment (left ventricle ejection fraction was greater than SO%), the right ventricular volumes were always greater than the left ones, and the right ventricular ejection fraction was invariably smaller than the left one. Familial occurrence was found in seven patients, belonging to tive families.

Endomyocardial biopsy in the cardiomyopathy patients was obtained via the femoral vein using the long sheath technique (disposable Cordis bioptome) and in the control patients via the right internal jugular vein (Caves-Schultz bioptome). Three to five biopsy specimens from each patient were fixed in 10% phosphate buffered formaline (pH 7.35%); 7 pm paraffin embedded sections were cut, and stained according to the Haematoxylin- Eosin and Azan-tri~hrome techniques to highli~t regions of fibrous tissue.

Using a Kontron IBAS II image analyser we evaluated the percent area of the following parameters: myocytes, fibrous and fatty tissue and interstitium (fibrous and fatty tissue excluded). The TV-camera signal was visualized in black and white (768 x 512 pixels), the image was stored and then analyzed (Fig. 1). Within the 256 gray levels analyzed by the system, three intervals were inter- actively fixed, and each one corresponded to one of the three parameters to be evaluated. Two trained observers defined the first interval (dark levels) which corresponded to the entire ‘myocytes area’; the second interval (inte~ediate levels) eor- responded to the ‘fibrous tissue area’ and the third (lightest levels) to the ‘interstitial and adipose area’ (Fig. 1).

215

Fig. 1. Endomyocardial biopsy from a control donor (a,b), dilated cardiomyopathy (c,d), and right ventricular cardiomyopathy

patient (e,f) as appeared on the computer screen in black and white, and in colours (red was for myocytes, blue for tibrous tissue and white for interstitium + fatty tissue). Azan stain, original magnification x400.

276

The interstitial space could be calculated by sub- tracting the readily identi~able fatty tissue from the total ‘interstitial and adipose area’.

Seven fields were randomly selected and studied at x 16 power to avoid any overlapping. Only fields in which the entire screen was occupied by tissue were chosen; each field was about 0.057 mm2.

Statistical analysis

The mean f S.D.s was calculated for all four histologic parameters in each patient group. The measurements were compared using the Student’s r-test for unpaired data.

We then calculated the 95% confidence intervals (mean f 2 S.D.) for each histologic parameter in all three groups. The truth in our test was represented by the clinical diagnosis. True positives were patients with disease whose biopsy data fell within the confidence limits, while true negatives were patients without disease whose biopsy data fell outside the confidence interval. False positives were patients whose biopsy data fell within the confidence interval, but did not have disease; false negative were patients with disease whose biopsy data did not fit within the confidence interval. Sensitivity and specificity were then separately assessed for one, two or three parameters taken together; we observed a certain overlapping between the confidence intervals of the parameters, As myocyte loss with extensive fibrous and fatty tissue substitution are features of right ventricular cardiomyopathy, we redefined the diagnostic values of the four parameters that

TABLE 1

Age and sex distribution of 89 patients studied.

Group Sex Age (years) (mean f SD.)

F M

Control 10 20 23.20 zt 9.12 (30 patients)

Dilated cardiomyopathy 8 21 40.37 * 13.07*

(29 patients) Right ventricular cardio- 14 16 35.03 f 14.67*

myopathy (30 ~tients)

*P < 0.01 versus control value.

typify this disease considering only those which were free of any overlapping.

Sensitivity and specificity were then calculated on the basis of these new intervals in order to verify whether any of the histologic parameters might be useful in identifying patients with right ventricular cardiomyopathy.

Results

Age and sex distribution in the 89 patients is reported in Table 1. There was no statistically significant age difference between dilated cardiomyopathy and right ventricular cardiomyopathy patients (40.37 f 13.07 vs. 35.03 f 14.67 years); patients in the control group (donor) were signi~cantly younger (23.20 f 9.12 years) (P < 0.01).

Table 2 shows the mean percent area i S.D.s

TABLE 2

Mean f SD. of the percentage area occupied by the four histologic parameters in the three groups.

Myocytes Interstitium Fibrous Fatty tissue tissue

Control 78.10 i 7.34*,** 13.20 f 4.31 8.10 f 3.s9t** 0.33 f 1.447 Dilated cardiomyopathy 63.39 f 9.22t 14.55 f 3.93 21.80 f 9.29 0.07 f 0.31t Right ventricular cardiomyopathy 47.28 f 15.01 14.56 f. 5.39 24.60 zt 11.37 13.30 f 17.30

*P < 0.05 vs. dilated cardiomyopathy. +*I’ < 0.01 vs. right ventricular cardiomiopathy. $P < 0.05 vs. right ventricular cardiomiopathy.

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TABLE 3

Mean f S.D. of the percentage area occupied by the four histologic parameters in the two right ventricular cardiomyopathy subgroups.

Right ventricular cardiomyopathy

Fibrous tissue + fatty tissue (20 patients)

Fibrous tissue (IO patients)

Myocytes tnterstitium

42.04 zt 12.91 14.11 f 5.82

57.74 * 13.83 15.46 f 4.54

Fibrous tissue

23.54 f 10.51

26.71 f 13.28

Fatty tissue

19.96 f 17.80

for the four histologic parameters considered in each patient group. In control group percentage of myocytes was 78.10 f 7.34; of interstitium 13.20 f 4.31; of fibrous tissue 8.10 f 3.89 and of fatty tissue 0.33 f 1.44 (observed in only two cases 7.73 f 21.87 and 2.43 f 6.43, respectively). In dilated cardiomyopathy percentage of myocytes was 63.39 f 9.22; of interstitium 14.55 f 3.93; of fibrous tissue 21.80 f 9.29, and of fatty tissue 0.07 f 0.31 (observed in only two cases, 1.72 f 3.69 and 0.41 f 1.00, respectively).

Statistically significant differences were observed between the control and dilated cardiomyopathy groups for myocytes loss (P < 0.05) and fibrous tissue increase (P < 0.05); no significant differences were observed for interstitium (P = N.S.) and fatty tissue (P = N.S.).

In right ventricular cardiomyopathy group the percentage area of myocytes was 47.28 f 15.01; of interstitium 14.56 f 5.39; of fibrous tissue 24.60 f 11.37; of fatty tissue 13.30 f 17.30 (observed in twenty cases).

Right ventricular cardiomyopathy showed a significant decrease in percent area of myocytes (versus control P-< 0.01; vs. dilated cardiomyopathy P < 0.05) and a significant increase in fatty tissue (vs dilated cardiomyopathy and control, P c 0.05). For fibrous tissue, the difference was statistically significant only when right ventricular cardiomyopathy was compared to the control (P < 0.05), whilst the percent area for fibrous tissue was nearly equal in the right ventricular cardiomyopathy and dilated cardiomyopathy groups. Again, significant differences were not observed for interstitium.

Fatty tissue was observed in 20 out of 30 right ventricular cardiomyopathy cases (66.66%), in two out of 30 control cases (6.66%) and in two out of 29 dilated cardiomyopathy patients (6.89%). The mean percent area for fatty tissue was 13.30 * 17.30 in right ventricular cardiomyopathy, 0.33 f 1.44 in the control group and 0.07 f 0.31 in dilated cardiomyopathy. The mean percent areas for the four parameters in right ventricular

TABLE 4

Myocytes. interstitium, fibrous tissue and fatty tissue confidence intervals (M f 2 SD.) obtained from control, dilated cardiomyopathy and right ventricular cardiomyopathy hearts.

Myocytes fnterstitium Fibrous Fatty

Control 63.42-92.78 4.58-21.82 0.32-15.88 O-3.21 Dilated cardiomyopathy 44.95-8 1.83 6.69-22.41 3.22-40.38 O-O.69 Right ventricular cardiomyopathy 17.26-77.30 3.78-25.34 1.86-47.34 O. l”-47.90

*As fatty tissue is a feature of right ventricular cardiomyopathy and is exceptionally rare in the two other groups, we chose 0.1 as the inferior limit of the confidence intervaf.

Fig. 2. Histograms of sensitivity and specificity of myocytes, interstitium, fibrous tissue and fatty tissue in identifying control (a), dilated cardiomyopathy (b), and right ventricular cardiomyopa~y (c) hearts. Values are expressed in percentages. Sepa- rate analyses were carried out for one, two, three, four

parameters.

cardiomyopathy cases in which fatty tissue was present or absent are reported in Table 3. In the cases in which fatty tissue was present, the mean percent area was 42.04 f 12.91 for myocytes, 14.11 i 5.82 for interstitium, 23.54 rf: 10.51 for fibrous tissue, and 19.96 i 17.80 for fatty tissue. In the 10 cases without fatty tissue we obtained a mean percent area of 57.74 f 13.83 for myocytes, 15.46 AZ 4.54 for interstitium, and 26.71 f 13.28 for fibrous tissue (Tabte 3).

The 95% confidence intervals for myocytes, interstitium, fibrous tissue and fatty tissue, obtained from control, dilated cardiomyopathy and right ventricular cardiomyopathy hearts are shown in Table 4.

The sensitivity and specificity of each single histologic parameter taken separately was determined in control hearts. The sensitivity was 96.67% for myocytes, interstitium, and fatty tissue, and 93.34% for fibrous tissue. In terms of specificity, whilst for myocytes was 69.00% and for fibrous tissue was 74.58%, for fatty tissue and interstitium was low (28.81% and 8.47%, res~tively). The ability of identifying abnormal hearts was even worse when the analysis was carried out for two, three or four parameters together. In fact specilicity for myocytes + fibrous tissue was 57.63%, for myocytes + fatty tissue was 28.81%, for myocytes + fatty + fibrous tissues was 20.34O/o and for myocytes + fatty + fibrous tissues + interstitium was 1.69%. The sensitivity was almost unaltered when two, three or four parameters were considered, varying from 96.67% to 100% (Fig. 2a).

In dilated cardiomyopathy sensitivity for one parameter was 96.55% for myocytes, interstitium and fatty tissue and 89.65% for fibrous tissue. Specilicity ranged from 11.66% for interstitium and ftbrous tissue, to 35.66% for fatty tissue and to 40% for myocytes, When two, three, or four parameters were considered sensitivity did not change whilst s~ci~city increased slightly. For myocytes + fibrous tissue sensitivity was 89.65% and s~ci~city was 41.66%, for myocytes + fatty tissue sensitivity was 96.55% and specificity was 53.33%, for myocytes + fatty tissue -t fibrous tissue sensitivity was 86.20% and specificity was 58.33%, and four for parameters sensitivity was 86.20% and specificity was 56.66%. Therefore the ability of excluding false positive was increased only slightly (Fig. 2b).

In right ventricular cardiomyopathy the sensitivity for one parameter was high for myo~ytes, interstitium and fibrous tissue (96.67%). It was considerably lower for fatty tissue (66.67%) since not all the patients have fatty in~ltration. On the contrary specificity was very high for fatty tissue (93.22%), but low for myocytes (28.81%), interstitium (O%), and fibrous tissue (1.69%).

219

Fig. 3. Confidence inervals for the four histologic parameters in the three groups expressed as percentage areas. By excluding any interval overlapping we obtain the new diagnositic values for right ventricular cardiomyopathy.

For two parameters sensitivity was 90.00% (myocytes + fibrous tissue) and 60.00% (myocytes + fatty tissue) while specificity was 74.57% (myocytes + fibrous tissue) and 93.22% (myocytes + fatty tissue); for the three parameters sensitivity was 56.66% and specificity 93.22%, for the four parameter values were 56.67% and 93.22%, respectively (Fig. 2~).

The diagnostic values typifying right ventricular cardiomyopathy obtained by excluding any sort of overlapping between confidence intervals of the

Fig. 4. Histograms of sensitivity and specificity of histologic parameters in diagnosing right ventricular cardiomyopathy ap- plying the new diagnostic intervals. (Values are expressed in percentages). Separate analyses were performed for one single parameter (a), two, three and four parameters (b).

three groups (Fig. 3) were myocytes ~44.95%; fibrous tissue >40.38%; fatty tissue >3.21%, and interstitium > 22.41% or < 4.58%, with a sensitivity of 66.66% and a specificity of 91.52% for at least one parameter (Fig. 4).

On this basis, 20 out of 30 right ventricular cardiomyopathy patients were classified correctly by histology (sensitivity 66.66%) while 10 patients were false negative. In the control group, only two patients were classified as affected by right ventricular cardiomyopathy (false positive), being in the first one interstitium 25.38% and in the second one fatty tissue 7.73%. In the dilated cardiomyopathy group, three patients were classified as affected by right ventricular cardiomyopathy (false positive), being in the first one interstitium 22.8%, in the second one fibrous tissue 42.63% and in the third one fibrous tissue 44.90% and myocytes 44.55%.

Discussion

In previous studies, we delineated the clinical and pathological profile of patients with right ventricular cardiomyopathy [l-9]. In the present investigation, we addressed the diagnostic accuracy of endomyocardial biopsy. To this end, we compared biopsy findings in three groups of patients, who were previously classified according to their clinical diagnosis, which was considered the truth to be tested [2-8,13-151. We chose dilated cardiomyopathy for comparison since this disease involves both left and right ventricles [ 16,171; biopsies, obtained from donor heart grafts 7 days after transplantation, constituted our control group, and were considered the most ‘normal’ specimens ethically obtainable.

The value of endomyocardial biopsy in the diagnosis of right ventricular cardiomyopathy is still undefined [10,18-241, as the presence of fatty or fibrous tissues is not in itself a pathognomonic histologic feature. In fact, patients with normal heart may have fatty tissue infiltration of the right ventricle [11,12]. On the other hand, heart disease may not be detectable (22-261, or only a mild increase in fibrous tissue may be demonstrated, in patients with paroxysmal ventricular tachycardia. Moreover, fibrosis is a common finding in endo-

280

myocardial biopsy of either the right or left ventricle in patients with dilated cardiomyopathy [27-311.

Histologic quantitative parameters to date have not been described as diagnostic criteria for right ventricular cardiomyopathy, and only a few reports have treated the histologic or ultrastructural substrates of the disease [32-381. To improve the possibility of achieving a correct diagnosis, the qualitative morphologic evaluation should be inte- grated by quantitative techniques, that ensure objective and reproducible values. Here we reported the mean values and 95% confidence intervals (defined as mean f 2 SD.) of the four most important histologic parameters, namely myocytes, interstitium, fibrous tissue and fatty tissue, obtained by means of an image analyser. We and others have previously used this method [40,41], which is easy and relatively non time- consuming. Interobserver and intraobserver variability, previously tested, were less than 2%.

To avoid the risk of perforating the right ventricular free wall, the endomyocardial biopsy technique theoretically aims at obtaining samples from the interventricular septum. This potentially life threatening risk is exacerbated in right ventricular cardiomyopathy because of the underlying fragile wall which is replaced by fatty tissue. Considering that the interventricular septum is usually spared by tibro-fatty replacement in right ventricular cardiomyopathy, our finding of a statistically significant difference between right ventricular cardiomyopathy and control in reference to fibrous and fatty tissue, is apparently surprising, but in agreement with Hasumi et al. who studied a group of nine patients with right ventricular cardiomyopathy undergoing right ventricular endomyocardial biopsy in the interventricular septum or in the apical region [42]. To explain our findings, which are as good as those obtained by target-directed endomyocardial biopsy [43], we may assume that the samples were obtained from the free wall of the right ventricle where the ante- rior wall joins the interventricular septum.

No complications occurred in this patient series during endomyocardial biopsy, nor were mesothelial cells, which would raise the suspect of

ventricular perforation, observed at histology. However, since mesothelial layers were seen in biopsies sent to us by other centers (unpublished data), endomyocardial biopsy in right ventricular cardiomyopathy patients should be carried out in specialized units with cardiac surgery stand-by, as the risk of perforation due to a thin and soft right ventricular free wall is very high.

Statistical analysis showed a significant difference between control hearts, and hearts with dilated cardiomyopathy and right ventricular cardiomyopathy as far as myocytes, fibrous tissue and fatty tissue were concerned. The percent area of myocytes shows a decrease in dilated cardiomyopathy, which is more marked in right ventricular cardiomyopathy; fibrous tissue is increased in the two and fatty tissue is characteristic of right ventricular cardiomyopathy.

There was a certain overlapping between the two diseases, which explains the very high sensitivity but the low specificity of our method. A very interesting finding in our study was that the fatty tissue parameter was almost exclusively present in right ventricular cardiomyopathy; in only one case of the control group, the percentage of fatty tissue reached 7.73%. In this regard, the donor hearts, which usually do not undergo angiographic evaluation before transplantation, were assumed to be normal because of the age and history of the patients. Fatty tissue in right ventricular cardiomyopathy was highly specific but poorly sensitive, because two subgroups were identified, one with fibro-fatty and another with isolated fibrous features. As the presence of fibrous tissue is common in dilated cardiomyopathy, this creates problems in achieving a correct diagnosis. To identify right ventricular cardiomyopathy, we determined new diagnostic values for each histologic parameters excluding any confidence interval overlapping. When these new diagnostic values were applied, for at least one of the four parameters, we obtained a mild sensitivity (67%) and a high specificity (90%). In the subgroup with fatty tissue replacement, the fatty component was more than 3.21%, and this means that when a higher amount of fatty tissue is quantified in endomyocardial biopsy of young patients, right ventricular cardiomyopathy

must be suspected. Equally the diagnosis of right ventricular cardiomyopathy can be achieved when fibrous tissue replacement exceeds 40.38%.

A limitation of the present investigation resides in the fact that two different endomyocardial biopsy techniques were performed in right ventricular cardiomyopathy and dilated cardiomyopathy patients and the control group, respectively. Endo- myocardial biopsy in the dilated cardiomyopathy and right ventricular cardiomyopathy groups were taken by the long sheath technique through a femoral approach, while biopsies from patients who underwent heart transplantation were obtained using right internal giugular approach. It was impossible to establish if the samples obtained with the two techniques were representative of the same topographical regions. However, this source of error was not present when we compared biopsies from the right ventricular cardiomyopathy and dilated cardiomyopathy since the same technique was employed in these two groups.

In conclusion, the aim of our study was to present convincing and objective evidence through morphometry. Quantification through a eye piece graticle, although less objective, could be applied to endomyocardial biopsy by taking the values we calculated as point of reference.

Acknowledgements

This work was supported by National Council for Research, Target Project “FAT.MA”, Rome, Target Project “BT.BS.“, Milan, Target project Aging, Rome and by Veneto Region, Target Pro- ject “Cardiomyopathy”, Venice, Italy. 14

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Endomyocardial biopsy in right ventricular cardiomyopathy